The aim of this proposal is to study the way in which replication of chromosomal DNA and protein synthesis is controlled according to the growth state of cells in order to understand how transformed and malignant cells escape these controls. In normal cells the decision to divide and, therefore, to replicate DNA is responsive to the cell's social environment so that as the cell density in culture increases, further DNA replication is restricted. Transformed cells do not respond to their environment in this manner, and it is hoped that an analysis of the sequence of events during DNA replication in normal and transformed cells may shed some light on this non-responsiveness. In particular, I am going to investigate the possibility that the loss of control in transformed cells is due to a divergence in the sequence of initiation of replicons from that in normal cells. Protein synthesis is depressed in normal cells in response to increasing cell density in a way which suggests that protein chain initiation is subject to regulation. In contrast, there does not appear to be a regulation of protein synthesis of this sort in transformed cells. I am going to examine whether the control of initiation is exerted at the level of binding of met tRNAf to the 40S ribosomal subunit or at some other step in the initiation cycle that precedes the binding of mRNA to the ribosomes. This investigation of the way in which chain initiation is regulated in normal cells will help me to determine how control is escaped by transformed cells.